The objective of this research is to study the mechanisms whereby experimental alterations in motor nerve function produce muscle disease. These are continuing studies of an experimental model of myopathy which may be acetylcholine-mediated. The models are produced by chronic inhibition of cholinesterase with organophosphorus agents and by enhancing the release of acetylcholine. Included are: 1) further studies on the selective vulnerability of tonic muscle to necrosis; 2) clarification of the earliest events, physiological and morphological, related to end-plate necrosis; 3) studies on the mechanism of adaptation to chronic cholinesterase inhibition; and 4) new studies to determine how alterations in axoplasmic flow and the electrochemical events of neurotransmission affect the experimental myopathies. The methods employed are: 1) histochemistry, 2) electrophysiology 3) biochemistry and 4) electron microscopy. The ultimate aim is to acquire insight into the linkage between neural dysfunction and myopathy. It is difficult to study the onset of human myopathies. Consequently, experimental myopathies must be developed and carefully examined to study the altered neural funtion leading to the initiation of a myopathy. Elucidation of neural control of muscle pathology will provide a sound experimental basis for drug development in the treatment of human muscle disease. BIBLIOGRAPHIC REFERENCES: Ranish, N., and W-D. Dettbarn. The effect of paraoxon on fast axoplasmic flow. Transactions of the American Society for Neurochemists, 7: 1976. Laskowski, M.B., W.H. Olson, and W-D. Dettbarn. Increased frequency of miniature end-plate potentials coincident with lesions of the motor end-plate. Fed. Proc. 35* 1976